Dynamic folding pathway models of the villin headpiece subdomain (HP‐36) structure

We have investigated the folding pathway of the 36-residue villin headpiece subdomain (HP-36) by action-derived molecular dynamics simulations. The folding is initiated by hydrophobic collapse, after which the concurrent formation of full tertiary structure and alpha-helical secondary structure is observed. The collapse is observed to be associated with a couple of specific native contacts contrary to the conventional nonspecific hydrophobic collapse model. Stable secondary structure formation after the collapse suggests that the folding of HP-36 follows neither the framework model nor the diffusion-collision model. The C-terminal helix forms first, followed by the N-terminal helix positioned in its native orientation. The short middle helix is shown to form last. Signs for multiple folding pathways are also observed.